A prospective, randomized study comparing cefepime and imipenem-cilastatin in the empirical treatment of febrile neutropenia in patients treated for haematological malignancies

A prospective, open label, randomized, multicentre study was conducted, comparing the efficacy and safety of cefepime with that of imipenem-cilastatin for the management of febrile neutropenia in patients with haematological malignancies. Furthermore, the safety of early discontinuation of antibiotic therapy in patients with fever of undetermined origin (FUO) was assessed. A total of 180 patients with 207 febrile episodes were randomized at start of fever (105 episodes for cefepime and 102 episodes for imipenem). The 2 groups were comparable in terms of age, gender, underlying malignancy, prior transplantation, and presence of central venous catheters. All patients were neutropenic at inclusion with median absolute neutrophil count (ANC) 0.1 x 10(9)/l(range 0-1 x 10(9)/l), and ANC < or = 0.1 x 10(9)/l in 77% of included patients. The mean duration of neutropenia, with ANC < 0.5 x 10(9)/l was 6.2 d. Febrile episodes were classified as microbiologically documented infection (47%), FUO (43%), or clinically documented infection (10%). At final evaluation 1-2 weeks after completion of antibiotic therapy, monotherapy success rates were 40% and 51% in the cefepime and imipenem-cilastatin groups respectively (p = 0.33). The 4-week overall mortality rate was 5%. Three (2%) of the cefepime treated patients and 4 (3%) of the imipenem-cilastatin treated patients died as a result of infection. Adverse events directly related to antibiotic treatment were uncommon and did not differ between groups. Early discontinuation of antibiotic therapy in 31 patients with FUO 48 h after defervescence was not associated with an increased rate of fever relapse or mortality compared with a subgroup of 29 patients where therapy was continued.     

Continuous infusion of ceftazidime for patients with breast cancer and multiple myeloma receiving high-dose chemotherapy and peripheral blood stem cell transplantation

This prospective study was performed to examine the safety and efficacy of a continuous infusion of ceftazidime in patients who developed febrile neutropenia after high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (PBSCT) and to determine if the underlying disease represents a risk factor for infectious complications. From September 1995 to May 2000, 55 patients with breast cancer (BC, group I, 54 females, one male) and 32 patients with multiple myeloma (MM, group II, 10 female, 22 male) were included in this study. The febrile patients received a 2 g intravenous bolus of ceftazidime, followed by a 4 g continuous infusion over 24 h using a portable infusion pump. If the fever persisted for 72 h a glycopeptide antibiotic was added. The median age was 42 years (range 22-59) in group I and 52 years (range 35-63) in group II. Thirty-five BC patients (64%) and 20 MM patients (63%) responded to the monotherapy with ceftazidime. After addition of a glycopeptide antibiotic, an additional 11 BC patients vs 10 MM patients became afebrile. The causes of fever in group I were fever of unknown origin (FUO) in 49 patients, microbiologically documented infection (MDI) in five patients, and clinically documented infection (CDI) in one patient. The causes of fever in group II were FUO in 22 patients, MDI in eight patients and CDI in two patients. Forty-one febrile episodes in BC patients (75%) and 22 episodes in the MM patients (69%) were successfully managed by out-patient treatment, resulting in a saving of an average of 20 days of inpatient care. Significantly more episodes of MDI and CDI occurred in patients with MM (P = 0.05). The results indicate that BC and MM patients with febrile neutropenia after HDCT and PBSCT can be treated as outpatients with close monitoring to ensure safety. This approach represents a better use of health care resources.     

Infectious Complication in 314 Patients after High-Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation: Risk Factors Analysis and Outcome

Abstract Background: Infectious complications occur in most of the patients receiving high-dose therapy (HDT) and autologous hematopoietic stem cell transplantation (HSCT). The objective of the study was to analyze of the type and incidence of infectious complications during neutropenia after HDT and autologous HSCT with respect to risk factors related to stem cell transplant setting in patients treated for hematological malignancies in a single center. Patients and Methods: A total number of 314 patients diagnosed for Hodgkin's disease (HD), non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), multiple myeloma (MM) or acute lymphoblastic leukemia (ALL) were included in the study. Analysis of risk factors and outcome of infections after HDT and autologous HSCT was performed. Results: Infectious complications during neutropenia after HDT occurred in 92.3% patients. Microbiologically documented infections (MDI) accounted for 38.9% of febrile episodes, clinically documented infections (CDI) for 9.3%, and fever of unknown origin (FUO) for 51.7% cases. Median time to defervescence with antibiotic therapy was seven days for FUO and nine days for documented infections (p < 0.001). Duration of infection correlated with the length of very severe neutropenia (p < 0.001). Response to first-line antibiotic therapy was seen in 34% patients. Infections were fatal in 12 (3.8%) patients. The highest probability of infection was observed for ALL and AML patients, especially these conditioned with total body irradiation (TBI). Conclusion: Patients at high risk of infection after autologous HSCT were identified as those with acute leukemia and those after conditioning with TBI, all with prolonged neutropenia. We suggest that newer prophylactic strategies should be administered to these groups of patients. Lidia Gil and Jan Styczynski contributed equally to this study.     

European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia

Owing to increasing resistance and the limited arsenal of new antibiotics, especially against Gram-negative pathogens, carefully designed antibiotic regimens are obligatory for febrile neutropenic patients, along with effective infection control. The Expert Group of the 4^th European Conference on Infections in Leukemia has developed guidelines for initial empirical therapy in febrile neutropenic patients, based on: i) the local resistance epidemiology; and ii) the patient’s risk factors for resistant bacteria and for a complicated clinical course. An ‘escalation’ approach, avoiding empirical carbapenems and combinations, should be employed in patients without particular risk factors. A ‘de-escalation’ approach, with initial broad-spectrum antibiotics or combinations, should be used only in those patients with: i) known prior colonization or infection with resistant pathogens; or ii) complicated presentation; or iii) in centers where resistant pathogens are prevalent at the onset of febrile neutropenia. In the latter case, infection control and antibiotic stewardship also need urgent review. Modification of the initial regimen at 72–96 h should be based on the patient’s clinical course and the microbiological results. Discontinuation of antibiotics after 72 h or later should be considered in neutropenic patients with fever of unknown origin who are hemodynamically stable since presentation and afebrile for at least 48 h, irrespective of neutrophil count and expected duration of neutropenia. This strategy aims to minimize the collateral damage associated with antibiotic overuse, and the further selection of resistance.     

Low-risk febrile neutropenia in a medical oncology unit

Background: Febrile neutropenia occurring in patients receiving chemotherapy for solid tumours or lymphoma is usually of short duration, and therefore may have a better outcome compared to patients with acute leukaemia or patients receiving myeloablative chemotherapy. Aims: To review retrospectively the outcomes for febrile neutropenia occurring in patients of the Medical Oncology Unit at our institution, and to identify factors associated with worse outcome, particularly prolonged admission or death. Methods: We reviewed 102 episodes of febrile neutropenia occurring in 85 patients treated between 1992 and 1994. Demographic factors, tumour-related factors and clinical aspects of the episodes were correlated with outcome. Results: The median age was 60 years (range, 18–87), with 56 (55%) episodes occurring in females. Twenty-eight (27%) episodes occurred in patients with lymphoma, with the remaining 74 (73%) occurring in patients with solid tumours. At presentation, the median absolute neutrophil count (ANC) was 0.14×10⁹/L with a median duration of significant neutropenia (ANC<0.5×10 ⁹/L) of three days. The median duration of fever was two days. Twenty-nine (28%) episodes had positive cultures; of these 11 had bacteraemia. Forty-four (43%) episodes were classified as unexplained fevers. The remaining 29 episodes were associated with clinically documented infection but negative cultures. There was a high treatment success rate (81%) with first-line empirical antibiotics. Of 19 treatment failures, 13 were due to the necessity for antibiotic modification; the other six patients died from infection. Factors associated with a worse outcome (including prolonged admission and death) include: diagnosis of lymphoma; increasing number of chemotherapy courses; early onset of neutropenia; pneumonia; severe hypotension; and multiple co-morbidities. Conclusions: Febrile neutropenia in adult patients with solid tumours or lymphoma is associated with a relatively good outcome, possibly due to the short duration of neutropenia. A future prospective study to validate the risk factors indentified in this study would be useful for defining patients at low risk for the adverse outcomes examined, in whom less intensive management for this condition may be possible.     

An assessment of the efficacy of antimicrobial prophylaxis in bone marrow autografts.

Fifty-three patients undergoing autologous bone marrow transplantation received antimicrobial prophylaxis with ciprofloxacin with or without erythromycin and low dose intravenous amphotericin B. Eight patients remained afebrile throughout the neutropenic period. All other patients had one or more febrile episodes. The median time to fever after the onset of neutropenia was 7 days. There were no gram-negative organisms isolated from blood cultures during any of these episodes whereas gram-positive organisms were isolated in 28. There was one death in this series associated with sepsis. The use of low-dose prophylactic parenteral amphotericin did not prevent the subsequent successful use of full dose amphotericin for antibiotic-resistant fever. Ciprofloxacin effectively prevents gram-negative sepsis. The addition of erythromycin does little to prevent gram-positive sepsis. The use of regimens with agents with activity against gram-positive organisms is appropriate initial treatment of all febrile neutropenic episodes.     

A pilot study of piperacillin and ciprofloxacin as initial therapy for fever in severely neutropenic leukemia patients.

We studied the efficacy of piperacillin and ciprofloxacin as initial parenteral therapy in 41 adult patients with leukemia who developed 47 febrile episodes during severe neutropenia following chemotherapy. 40 patients (98%) survived their febrile episode(s), whereas 1 patient died of infection. When assessed at 72 h after initiation of treatment (early evaluation), 24/47 episodes (51%) had been successfully treated. These 24 favourable responses were seen in 15/24 (63%) microbiologically documented infections and 9/19 (47%) fever of unknown origin (FUO). At the resolution of fever (late evaluation) 46 episodes were evaluable, and 28 (61%) had responded successfully to piperacillin and ciprofloxacin. Successful treatment was most frequently observed in microbiologically defined infections, 18/23 (78%). Three of 5 (60%) Gram-positive, 11/12 (92%) Gram-negative and 1 of 2 mixed bacteremias were successfully treated. In contrast, only 10/19 (53%) FUO and none of 4 clinically defined infections had responded. Thus, this pilot study indicates that piperacillin and ciprofloxacin may be a safe and effective combination for the treatment of febrile episodes in severely neutropenic leukemia patients, which merits further investigation in randomized trials.     

Tigecycline in febrile neutropenic patients with haematological malignancies: a retrospective case documentation in four university hospitals

Objectives

Tigecycline (TGC) is a first-in-class glycylcycline with an expanded spectrum of activity. Although TGC has not been prospectively studied in febrile neutropenia (FN), we observed that occasionally critically ill neutropenic patients unresponsive to other antibiotics were treated with TGC in our departments. The aim of our study was to analyse effectiveness and toxicity of TGC in FN.

Methods

Data of infectious episodes treated with TGC were retrospectively collected. Baseline data of patients, haematological malignancy, infection and adverse events were documented. Success was defined as defervescence (≥7 days) in the absence of any sign of persistent infection.

Results

Data of 35 patients with haematological malignancies and FN were evaluated. Median duration of neutropenia was 25 days (range 6–69 days). The type of infection was pneumonia in 24 patients, four microbiologically documented infections, three clinically documented infections and four with fever of unknown origin. The TGC was administered after a median of two (range 1–5) prior antibiotic regimens. Treatment was successful in 15 (43 %) patients. In patients with prolonged neutropenia (≥28 days), response was significantly lower (13 vs. 79 %; p = 0.001). Eight (23 %) patients died during the fever episode. Grade 3–4 toxicity occurred in five (14 %) patients.

Conclusion

Our results showed promising response rates to TGC and very low toxicity rates compared to the generally low response rate of third-line antibiotic therapies, indicating that TGC may be a successful alternative for salvage treatment of febrile neutropenia, but further study is needed.     

Usefulness of G-CSF in pediatric high risk cancer patients with fever and neutropenia

Chemotherapy associated febrile neutropenia is an important cause of morbidity and mortality in pediatric patients with cancer. The use of granulocyte-colony stimulating factor (G-CSF) post chemotherapy decreases the risk of infectious complications but its efficacy during the febrile neutropenic episode remains controversial. Thirty five episodes of high-risk febrile neutropenia were randomized into two treatment arms, 18 received antibiotics and G-CSF (group A) and 17 received antibiotics only upon admission (group B). Both groups were comparable in terms of demographic and clinical characteristics. No significant differences between groups were found in duration of hospitalization (mean group A 7 vs group B 8 days), antibiotic treatment (mean 7 vs 8 days), fever (3 vs 2 days), nor of neutropenia (4 vs 3 days). One patient in group A died after RSV infection. Considering these results and a literature review, we propose that G-CSF should not be recommended in children during the course of their febrile neutropenic episode.     

Piperacillin/tazobactam vs ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial

Piperacillin/tazobactam was compared with ceftazidime for the empirical treatment of febrile neutropenia in patients with acute leukemia or following autologous peripheral blood stem cell transplantation. Owing to inclusion criteria, it was possible for the same patient to be randomized several times. A total of 219 individual patients were admitted to a prospective randomized clinical study: 24 patients were included twice. Patients (23.5%) remained afebrile. Patients who developed febrile neutropenia were randomized to receive intravenous ceftazidime (n = 74 patients, group I) or piperacillin/tazobactam (n = 87 patients, group II). Response to first-line antibiotic treatment was seen in 55% (group I) and 53% (group II). After the addition of vancomycin, a further 19% (group I) and 24% (group II) of the patients became afebrile. Causes of fever were: microbiologically documented infection in 36 and 34 patients of group I and II; Clostridium difficile in eight and 12 patients of group I and II, and fever of unknown origin in 30 and 41 patients of group I and II. One patient died in each group. Single-agent therapy with piperacillin/tazobactam is as effective as ceftazidime in the treatment of neutropenic fever and is well tolerated. Direct and indirect costs of both treatment regimes are equivalent.     

Patterns of infection in patients with aplastic anemia and the emergence of Aspergillus as a major cause of death.

Patterns of infection were studied in 150 patients with aplastic anemia who were admitted to the Clinical Hematology Branch, National Institutes of Health, between January 1978 and December 1989 for immunosuppressive therapy. Sixty percent of the patients were males, 71% were white, their mean age was 33.6 years (median, 27.5; range, 1-75), and 83% had severe aplastic anemia. One hundred three patients developed 1 or more febrile episodes during the study period. The risk factors for developing a febrile episode included a low Absolute Neutrophil Count (ANC) and Absolute Monocyte Count (AMC) at admission and the presence of an indwelling central venous catheter (Hickman-Broviack or Port-A-Cath). A total of 289 febrile events were studied, including unexplained fever (FUO) in 89 (31%), microbiologically documented infection (MBDI) in 137 (47%), and clinically documented infection (CDI) in 63 patients (22%). Compared to documented infections (MBDI) or CDI), FUO events were associated with a higher frequency of rigors, signs and symptoms of serum sickness, and treatment regimens known to cause fevers. None of the FUO events had a fatal outcome, even if the antibiotic therapy was discontinued before day 7. Among CDI events, bacteria were the most commonly defined etiologic agent (67%), followed by fungi (23%), viruses (7%), and parasites (3%). The patterns of bacterial infections in patients with aplastic anemia were similar to those observed in patients with cancer-related neutropenia. Twenty-one patients (15%) developed invasive fungal infections (aspergillus, 11; candida, 7; and both, 3), which were fatal in 19 (90%). Fungal infections accounted for 30% of the secondary infectious events and for 55% of fatal infectious events. The only identifiable risk factors for developing a fungal infection were the degree of neutropenia and monocytopenia at initial admission or final evaluation. Invasive pulmonary aspergillosis developed despite empirical amphotericin B therapy and was associated with a high incidence of fatal pulmonary hemorrhage (10 of 13 patients [77%]). Infection was responsible for 36 (62%) of the deaths observed during the study period and hemorrhage alone for 4 (7%). However, 20 of the patients who died of infection had concomitant hemorrhage. No significant drop in ANC, AMC, or platelet count could be demonstrated during a fatal infectious event as compared to a nonfatal infectious event. Invasive fungal infections, predominantly with aspergillus and candida, emerged in our study as the major causes of mortality in patients with aplastic anemia. Without bone marrow recovery the prognosis associated with invasive mycoses was grave.     

Duration of empiric antibiotic therapy in granulocytopenic patients with cancer.

Early initiation of empiric antibiotic therapy in febrile cancer patients has become established practice, but the appropriate duration of antibiotic therapy when no infectious source can be identified is unknown. The complications of broad-spectrum antibiotics argue for brief treatment, but the risk of an inadequately treated infection in the granulocytopenic patient favors longer therapy. We prospectively studied 306 episodes of fever and granulocytopenia in 143 patients with leukemia or solid tumor (age one to 33 years) with respect to the duration of empiric antibiotic treatment. Eligible patients (fever > 38 °C three times/24 hours or > 38.5 °C once, plus polymorphonuclear leukocytes < 500/mm³) had an extensive diagnostic evaluation, including at least two preantibiotic blood cultures, and therapy was then started with a broad-spectrum antibiotic regimen— Keflin^®, gentamicin and carbenicillin (KGC). Initial evaluation failed to identify an infectious etiology for the fever in 142 of 306 (46 per cent) episodes. Fifty-six of 142 (39 per cent) of these fevers of unknown origin were associated with persistent granulocytopenia for more than seven days; in 33 of these, defervescence occurred while the patients received KGC. After seven days of empiric KGC therapy, the 33 patients with fevers of unknown origin who had become afebrile with empiric antibiotics but whose polymorphonuclear leukocytes remained less than 500/mm³ were randomized to either continue or discontinue ($\text{d}\text{c}$) to receive KGC. The patients who continued to receive KGC until their polymorphonuclear leukocytes were more than 500/mm³ had no infectious sequelae. However, in seven of 17 (41 per cent) of the patients randomized to $\text{d}\text{c}$ KGC infectious sequelae developed (p = 0.007) within a median of two days of discontinuing KGC (two with fever which again responded to KGC therapy, and five with a documented infection [two ultimately fatal]). In none of the patients did a resistant microbial flora or superinfection develop. These data suggest that the patient with a fever of unknown origin who becomes afebrile during empiric antibiotic therapy may profit from continued therapy while granulocytopenia persists.     

Early hospital discharge with oral antimicrobial therapy in patients with hematologic malignancies and low-risk febrile neutropenia

Although consensus exists relating criteria for the identification of low-risk patients with febrile neutropenia, no clear indication on how to manage these patients has been so far provided particularly in outpatients affected by hematologic malignancies. The feasibility and safety of early discharge was prospectively evaluated in 100 outpatients with hematologic malignancies and febrile neutropenia. A strategy considering the risk-index of the Multinational Association of Supportive Care in Cancer (MASCC) was applied. High-risk patients were entirely managed at hospital. Low-risk patients were early discharged if they were afebrile since 48 h and not on supportive therapy requiring hospitalization. Out of 90 low-risk episodes, in 69 instances (76.7%), patients were discharged after a median of 4 days and continued home therapy with oral cefixime (78%) or other antibiotics. Only five outpatients (7.2%) had fever recurrence. Twenty-one low-risk patients were not early discharged due to worsening conditions (three deaths), need of multiple daily dose therapy, or discharge refuse. No clinical characteristic was able to predict the eligibility for early discharge. The MASCC risk-index is a useful aid in the identification of high-risk febrile neutropenia needing whole in-hospital treatment. As for low-risk patients, hospitalization at least in the first days of fever is required. Cefixime could be included among the oral antibacterial drugs to be used in the outpatient treatment of adult patients with febrile neutropenia.     

High-risk febrile neutropenia in Auckland 2003-2004: the influence of the microbiology laboratory on patient treatment and the use of pathogen-specific therapy

Background: International guidelines recommend routine microbiological assessment of patients with febrile neutropenia, but do not recommend a change from broad-spectrum antibiotic therapy to pathogen-specific therapy when a clinically relevant organism has been isolated. The aim of the study was to determine the aetiology of febrile neutropenia in adult haematology patients at Auckland City Hospital, to document the changes in treatment made following isolation of a clinically relevant organism and to assess adverse outcomes in any patient who received pathogen-specific therapy after a positive culture result. Methods: The results of all microbiological tests together with antibiotic therapy were recorded from consecutive patients with fever and a neutrophil count <0.5 × 10⁹/L over 1 year beginning in May 2003. Results: One thousand one hundred and ninety-six specimens were collected from 81 patients during 116 episodes of febrile neutropenia. A pathogen was isolated from blood cultures in 40 episodes: Gram-positive cocci accounted for 46% of isolates and Gram-negative bacilli for 35%. Isolation of a pathogen from blood cultures resulted in a change of treatment in 25 of 40 (62.5%, 95%CI 46–77%) episodes. In 12 of these episodes, antibiotic therapy was optimized to a single pathogen-specific agent. No adverse events or subsequent changes in antibiotic therapy occurred in any of these 12 patients. Isolation of a pathogen from specimens other than blood seldom led to a change in therapy. Conclusion: Isolation of a pathogen from blood cultures often allows antibiotic therapy to be simplified to a pathogen-specific regimen. Further study of this approach is warranted.     

Endotoxaemia and inflammatory mediators in febrile patients with haematological disease

Abstract. Objectives . To study the pattern of plasma levels of endotoxin, tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and C-reactive protein (CRP) in febrile neutropenic patients and to assess the potential diagnostic value of these analyses. Design . Consecutive prospective study. Setting . Patients treated at the haematology ward at Danderyd Hospital, Sweden. Subjects . Ninety-four patients with fever and haematological disease entered the study (male/female: 59/35) with 176 febrile episodes. Interventions . Blood samples were drawn at days 0, 1, 2 and 6 after onset of fever for analysis of, endotoxin, TNF-α, IL-6 and CRP. Results . Infectious aetiology was established in 62.5% of the febrile episodes. Blood cultures showed significant growth in 71/176 (40.3%) febrile episodes. Nonbacteraemic bacterial infections were diagnosed in 34/176 (19.3%) episodes. Endotoxin was detected in plasma in 40% of febrile episodes regardless of aetiology. TNF-α was detected in 61% and IL-6 in 94% of all febrile episodes. The initial TNF-α and IL-6 levels were significantly higher in patients with Gram-negative bacteraemia than in patients with other causes of fever (P < 0.001). In episodes evaluated as successful after empirical antibiotic treatment, a significant (P < 0.001) decrease in CRP concentrations were found on day 6 after onset of fever. Conclusions . The sustained, low-grade endotoxaemia and persistently elevated levels of TNF-α and IL-6 found in febrile patients may reflect a failing mucosal barrier that allows endogenous bacterial products to reach the circulation. The diagnostic value of endotoxin, TNF-α, IL-6 and CRP to discriminate between bacteraemic and nonbacteraemic febrile episodes was very limited. The study supports the present policy of broad, empirical antibiotic treatment in patients with haematological disease and fever.     

Clinical Infections and Bloodstream Isolates Associated with Fever in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia

Summary Background: Patients with acute myeloid leukemia (AML) are at high risk for infections. The aim of this study was to identify the sources of fever and the type of pathogens that cause bloodstream infection in patients with AML undergoing cytotoxic chemotherapy and antibiotic prophylaxis. Patients and Methods: The source of fever and the type of pathogens causing bloodstream infection were identified for 129 febrile episodes experienced by 42 patients with AML receiving cytotoxic chemotherapy and antibiotic prophylaxis. Results: A source of fever was identified in 81% of all febrile episodes. Mucositis (21.7%), pneumonia (13.2%), central venous catheter infection (12.4%), neutrophenic enterocolitis (9.3%) and invasive fungal disease (9.3%) were the most common sources of fever. Of 16 central venous catheter infections, seven (43.8%) were not associated with local signs. 49 febrile episodes (37.9%) were associated with bloodstream infections, of which 14 (28.6%) were polymicrobic and seven (14.3%) had an undefined source of infection. Bloodstream infection was commonly associated with cellulitis (60%), mucositis (57.1%), central venous catheter infection (55.6%), neutropenic enterocolitis (41.7%) and invasive fungal disease (41.7%). Gram-positive microorganisms were the most common blood isolates (75.8%). Gram-negative bacteremic infections occurred in eight episodes (12.1%) experienced by patients who were nor receiving ciprofloxacin prophylaxes at the time of bacteremia. Noninfectious sources of fever accounted for 23 (17.8%) of the 129 febrile episodes. Conclusion: Although the spectrum of pathogens that cause infection in this group of patients has shifted from gram-negative to gram-positive bacteria, the most common sources of infection remain the same as previously described and they mainly involve integumental surfaces. Received: December 5, 1999 · Revision accepted: August 8, 2000     

Candidemia in Patients with Body Temperature Below 37°C and Admitted to Internal Medicine Wards: Assessment of Risk Factors

Background

An increasing number of candidemia episodes has been reported in patients cared for in internal medicine wards. These usually older and frail patients may not be suspected as having candidemia because they lack fever at the onset of the episode. To identify the risk factors associated with the lack of fever at the onset of candidemia (ie, the collection of the first positive blood culture for Candida spp.) in patients cared for in internal medicine wards, we compared 2 group of patients with or without fever.

Methods

We retrospectively review data charts from 3 tertiary care, university hospitals in Italy, comparing patients with or without fever at onset of candidemia. Consecutive candidemic episodes in afebrile patients and matched febrile controls were identified during the 3-year study period. Patient baseline characteristics and several infection-related variables were examined. Random forest analysis was used, given the number of predictors to be considered and the potential complexity of their relations with the onset of fever.

Results

We identified 147 candidemic episodes without fever at onset and 147 febrile candidemia episodes. Factors associated with the lack of fever at onset of candidemia were diabetes, Clostridium difficile infection, and a shorter delta time from internal medicine wards admission to the onset of candidemia. The only variable associated with fever was the use of intravascular devices. Quite unexpectedly, antifungal therapy was administered more frequently to patients without fever, and no differences on 30-day mortality rate were documented in the 2 study groups.

Conclusions

Clinicians should be aware that an increasing number of patients with invasive candidiasis cared for in internal medicine wards may lack fever at onset, especially those with diabetes and C. difficile infection. Candidemia should be suspected in patients with afebrile systemic inflammatory response syndrome or in worsening clinical condition: blood cultures should be taken, and a timely and appropriate antifungal therapy should be considered.     

Short courses of antibiotics in selected febrile neutropenic patients.

To evaluate their policy of discontinuing broad spectrum antibiotics in patients with negative cultures who become afebrile but remain neutropenic, the authors retrospectively reviewed the charts of all pediatric patients diagnosed with cancer between 1980 and 1986. Two hundred seventy-one children had 385 admissions for infectious complications during the study period. In 39 of those episodes (9%), the patients had negative cultures, became afebrile, and were discharged with absolute neutrophil counts of less than 1000 cells/mm3 (mean 390 cells/mm3). They received relatively short courses of antibiotics with a median duration of 4 days. Only four of these patients became febrile during the followup period and there were no fatalities. Given the benign course of these patients, recommendations for prolonged antibiotic courses should be reconsidered.     

Infectious complications of chemotherapy in clinically aggressive mature B and T cell lymphomas

BackgroundScientific literature on infectious complications of chemotherapy in lymphomas is often based on retrospective studies or clinical trials performed with selected patients. This population may not be representative of the routine clinical practice. We aimed to analyse the incidence and type of infections associated to standard chemotherapy in clinically aggressive mature B and T cell lymphomas (AMBTL) and to detect baseline variables predictive of the risk of infection in a cohort of unselected patients.MethodsA prospective observational study of all the patients treated with first line chemotherapy for AMBTL in our Lymphoma Unit, in the setting of a community based teaching hospital, was performed. The statistical methods were univariate and multivariate analyses.Results183 infectious episodes were registered in 97 (49%) of the 198 patients. Seventy-nine of them (43%) were associated to febrile neutropenia (27% of the patients). Microbiological documentation was obtained in 46% and only clinical documentation in 15%; 39% were classified as fever of unknown origin. Gram negative bacilli were the predominant aetiology. There were several variables related to risk of infection, but in multivariate analysis only a poor initial performance status was predictive of the risk of febrile neutropenia and infection during the first line chemotherapy.ConclusionsIn our cohort of AMBTL patients treated with first line chemotherapy, more than half of the relevant infections occurred without febrile neutropenia. A poor performance status was the only independent variable associated with the risk of febrile neutropenia or infection in the course of first line chemotherapy.     

Filgrastim for cladribine-induced neutropenic fever in patients with hairy cell leukemia

Cladribine treatment of hairy cell leukemia (HCL) is complicated by neutropenic fever in 42% of patients despite documented infections being relatively uncommon. We performed a study of priming filgrastim followed by cladribine and then filgrastim again to determine if filgrastim would lead to a reduction of neutropenia and febrile episodes. Thirty-five patients received filgrastim and cladribine and were compared with 105 historic controls treated with cladribine alone. Cladribine was administered at 0.1 mg/kg/d by continuous infusion for 7 days. Filgrastim was administered at 5 micrograms/kg/d subcutaneously on days -3, -2, and -1 and then again after the completion of cladribine until the absolute neutrophil count (ANC) was >/=2 x 10(9)/L on 2 consecutive days (days +8, +9, etc). After filgrastim priming, the median ANC increased from 0.9 x 10(9)/L to 2.26 x 10(9)/L (2.5-fold increase), and after cladribine, the median nadir ANC in the filgrastim-treated group was 0.53 x 10(9)/L compared with 0.29 x 10(9)/L among historic controls (P =. 04). The median number of days to an ANC greater than 1.0 x 10(9)/L was 9 days in the filgrastim-treated group versus 22 days among historic controls (P < 10(-5)). The percentage of febrile patients, number of febrile days, and frequency of admissions for antibiotics were not statistically different in the two groups. Filgrastim regularly increases the ANC in patients with HCL and shortens the duration of severe neutropenia after cladribine. This phase II study, with comparison to historical controls, failed to detect any clinical advantage from the use of filgrastim and cladribine in the treatment of HCL. Accordingly, the routine adjunctive use of filgrastim with cladribine in the treatment of HCL cannot be recommended.